3alcineurin is a calcium regulated serine/threonine protein phosphatase. The calcineurin signal transduction pathway is involved in developmental and homeostatic regulation of a wide variety of cell types. We have recently described a new family of proteins that are enriched in heart and skeletal muscle called Modulatory Calcineurin-lnteracting Proteins (MCIPs). These proteins can form a physical complex with the active site of calcineurin and inhibit phosphatase activity. In turn, transcription of the mammalian MCIP1 gene is activated by calcineurin. Our goals are driven by the primary hypothesis that the MCIP family of proteins function as endogenous modulators of calcineurin activity. In initial studies we have shown that transgenic mice with elevated expression of human MCIP1 in cardiomyocytes are resistant to a variety of hypertrophic stimuli. Future development of measures to increase expression or activity of MCIP proteins selectively within the heart may have clinical value for prevention of heart failure. The goals of this grant are: 1) To define the interaction of MCIP with calcineurin, 2) To examine changes in the expression of MCIP genes and in the level of MCIPprotein during cardiac and skeletal muscle remodeling in order to refine our model integrating MCIP transcription, MCIP protein stability and calcineurin activity 3) To examine the cardioprotective potential of MCIPs and test our model that MCIPs are endogenous regulators of calcineurin signaling. These studies will clarify the mechanism, regulation and physiological role of MCIP proteins and create the basis for novel therapeutic approaches to regulating calcineurin.